Children with Idiopathic Short Stature Are Poor Eaters and Have Decreased Body Mass Index

Children With Idiopathic Short Stature Are Poor Eaters and Have Decreased Body Mass Index

Stefan A. Wudy*; Sandra Hagemann, MD*; Astrid Dempfle, PhD‡; Gundula Ringler, MSC‡; Werner F. Blum*§; Lars D. Berthold, MD࿣; Gerhard Alzen࿣; Ludwig Gortner¶; and Johannes Hebebrand#

ABSTRACT. Objective. In children with idiopathic s.org/cgi/doi/10.1542/peds.2004-1684; eating behavior, short stature (ISS), studies investigating body mass index short stature, body mass index, leptin, ghrelin. (BMI) or parameters of satiety regulation are scarce, and studies analyzing eating behavior are lacking. Methods. We recruited 214 children (123 index cases ABBREVIATIONS. CDGP, constitutional delay of growth and and 91 siblings) with ISS from 123 families. Affected puberty; FSS, familial short stature; ISS, idiopathic short stature; IGF-I, insulin-like growth factor I; IGFBP-3, insulin-like growth children had to have a body height <5th percentile, or, in factor–binding protein 3; CEBQ, Child Eating Behavior Question- the case of siblings, the body height of 1 child had to be naire; SDS, standard deviation score; LFFQ, Leeds Food Fre- <5th percentile and the other <15th percentile. Medical quency Questionnaire. histories were recorded by using structured and standardized interviews. Eating behavior was assessed by using the Child Eating Behavior Questionnaire. Percent hort stature is the most common cause for re- energy intake as fat was assessed by using the Leeds ferrals to pediatric endocrinologists. Many of Food Frequency Questionnaire. Endocrine markers of these patients have no identifiable medical ab- body weight regulation (leptin, ghrelin) were determined S normality and are classified with diagnoses such as in serum. constitutional delay of growth and puberty (CDGP), Results. Compared with population norms, BMI was -؊ familial short stature (FSS), or idiopathic short stat significantly lower (mean: 0.33 standard deviation ure (ISS). For most of these patients, the etiology of score). Furthermore, there was decreased food responsiveness (mean Child Eating Behavior Questionnaire their short stature is currently unknown, although it score: 1.9; population mean: 2.4), reduced enjoyment of is believed that genetic variations are the underlying food (3.2 vs 3.9), emotional undereating (2.6 vs 3.0), lower cause.1,2 In young children, CDGP is typically de- desire to drink (2.0 vs 2.8), and increased fussiness over fined by short stature (height below the third age- food (3.2 vs 2.9). When the sample was subdivided into and gender-specific percentile), bone-age retardation the 2 groups of “good” and “poor” eaters according to the of at least 1 year, and a positive family history of mothers’ assessment of the current eating behavior, re- delayed growth and pubertal development; how- duction in BMI as well as the behavioral characteristics ever, in a strict sense, the diagnosis cannot be made already delineated in the total sample were found to be before the time of puberty, when a delay in sexual even more consistent in the subgroup of poor eaters. In maturation becomes evident. Patients with FSS re- the total sample of our children, as well as in both subgroups, serum leptin (adjusted for gender, BMI, and Tan- veal a family history of short stature, whereas osse- ner stage) was found to be moderately raised but did not ous development and sexual maturation are appro- differ between poor and good eaters. Total serum ghrelin priate for chronological age. In case both bone age was not different between poor and good eaters. and parental height are within the normal range Conclusions. Our clinical, behavioral, and endocrino- (although often at the lower end), a diagnosis of ISS logic findings in patients with ISS point to an altered in its narrow meaning can be made. In clinical terms, eating behavior that possibly contributes to their short however, these individual diagnostic categories of- stature. Pediatrics 2005;116:e52–e57. URL: www.pediatric- ten can not clearly be distinguished, resulting in combined diagnoses. We therefore chose to summa- rize all these subtypes under the general term and From the Departments of *General Pediatrics and Neonatology and ࿣Pedi- broader definition of ISS. atric Radiology, Center of Child and Adolescent Medicine, Justus Liebig In a previous study from our hospital conducted University, Giessen, Germany; ‡Institute of Medical Biometry and Epide- ϭ miology, Philipps University, Marburg, Germany; §Eli Lilly and Company, between 2000 and 2002 (n 220), 70% of patients Bad Homburg, Germany; ¶Department of General Pediatrics and Neona- with short stature were classified as ISS (wider tology, University of the Saarland, Homburg, Germany; and #Department meaning, see above), with 25% having CDGP, 7% of Child and Adolescent Psychiatry, Rheinische Kliniken Essen, Universita¨t having FSS, 30% having a combination of CDGP and Duisburg-Essen, Essen, Germany. Accepted for publication Dec 29, 2004. FSS, and 8% having ISS in the narrow meaning. The doi:10.1542/peds.2004-1684 large overlap between CDGP and FSS points to a No conflict of interest declared. close relationship between these conditions. It has Address correspondence to Stefan A. Wudy, Center of Child and Adoles- already been hypothesized that CDGP and FSS are cent Medicine, Justus Liebig University, Feulgenstrasse 12, D-35392 Gies- likely to present either a single population with a sen, Germany. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Acad- continuum of skeletal age delay and parental stature emy of Pediatrics. or 2 largely overlapping populations.3 Pedigree anal-

e52 PEDIATRICS Vol. 116Downloaded No. 1 July from 2005www.aappublications.org/news www.pediatrics.org/cgi/doi/10.1542/peds.2004-1684by guest on September 28, 2021 ysis in patients with CDGP suggested strong familial been a poor eater? (ie, has your child ever eaten or drunk poorly aggregation.4 for at least 4 weeks?)” The options provided for answering this question were “yes,” “no,” “unknown,” or answer denied. Clas- Many pediatric endocrinologists have conceived sification of the children as “poor” or “good” eaters was based on the impression from their daily routine that children their current situation. with CDGP as well as those with FSS or ISS tend to Body height was measured to the nearest 0.1 cm by using an be lean4–6 and are often characterized as poor and Ulm Stadiometer (Busse, Ulm, Germany). A So¨hnle type 7723 fussy eaters by their parents. Most research has con- digital portable scale (capacity of 250 kg, precision of 0.1 kg) was 7 used for measuring body weight. Pubertal development was char- centrated on aspects such as final height or adjuvant acterized according to Tanner stage (pubic hair and breast devel- therapy.8,9 With the exception of a single study of opment in girls, testicular volume and genital development in prepubertal children with ISS,10 in which signifi- boys). Body height and BMI (kg/m2) were compared with the cantly lower body mass index (BMI) values were most current German reference data from Ͼ34 000 children and adolescents.12 Target height was calculated according to Tanner et found, data regarding systematic characterization of al.17 Bone age was assessed independently by 3 pediatric radiol- BMI and eating behavior are lacking. This is surpris- ogists according to the method of Greulich and Pyle18 from radio- ing, because suboptimal nutrition in childhood has graph films of the left hand. Bone-age determination was per- been suggested to contribute to the onset and persis- formed blinded for the patients’ birth date, and the mean of 3 tence of failure to thrive.11 Therefore, it was our aim ratings for each radiograph was used. The interobserver agreement was very good as judged from pairwise Bland-Altman bias in the present study to systematically delineate eat- plots,19 in which mean differences between 2 raters were between ing behavior, BMI, and endocrine parameters of 0.5 and 2.3 months and 95% limits of agreement were between 14 body weight regulation. and 24 months. If available, radiograph films from earlier presentations at our outpatient clinic were considered as well (1–6 ra- SUBJECTS AND METHODS diograph films were available per child), and the mean and maximal bone-age retardations at different time points were Study Population calculated. All children who presented between November 2001 and Au- IGF-I, IGFBP-3,20 leptin,21 and total ghrelin (Linco Research Inc, gust 2003 at the endocrine outpatient clinic of the Children’s St Charles, MO) were measured in our endocrinologic laboratory. University Hospital of Giessen (Giessen, Germany) and were di- All other parameters were measured by routine methods in our agnosed as having ISS served as index patients and were prospec- hospital’s laboratory for clinical chemistry. For IGF-I and IGFBP-3, tively enrolled in our study. The term “ISS” is used in this report gender- and age-dependent standard deviation score (SDS) values as the overarching diagnosis, indicating that the etiology of short were calculated,20 and leptin was transformed to SDS values ac- stature in these patients was unknown. It included patients who cording to gender, BMI, and pubertal stage.22 were diagnosed as CDGP, FSS, or a combination of both; however, it excluded patients who were born short for gestational age. Data Analysis Additional index cases were recruited retrospectively from our hospital database and comprised children with ISS who had at- Because our sample comprised both single children and pairs of tended our endocrine outpatient clinic between 1996 and 2001. siblings, not all observations were independent; consequently, The families of the index cases were contacted by phone, and the group means considering all children would give incorrect esti- whole family was invited to participate in the study, which was mates of underlying population means. Therefore, to calculate the conducted in our clinical endocrine research unit. In total, 214 appropriate means (as well as means for subgroups, eg, good and children with ISS from 123 families were recruited for the inves- poor eaters) for different variables, we used a linear model (anal- tigation, including 123 index cases and 91 siblings. The study ysis of variance), which included family as an independent fixed protocol was approved by the ethics committee of the Justus factor (with subgroup as an independent random factor if appli- Liebig University of Giessen, and written informed consent was cable) and calculated marginal means over families. Using the obtained from the parents. same model, we also tested for differences between subgroups. LFFQ data were available only for 103 index patients (who are Inclusion Criteria independent) and were compared between subgroups by using an unpaired t test. Data analysis was performed by using SPSS 11.0 To be included in the study, patients had to have a body height (SPSS Inc, Chicago, IL). Ͻ5th percentile,12 or, in the case of siblings, the body height of 1 child had to be Ͻ5th and the other Ͻ15th percentile. Only white and nonconsanguineous families were considered. The gestational RESULTS history had to be uneventful and birth weight had to be Ͼ3rd Our sample of 214 children included 56 cases 13 percentile for gestational age. Children with dysmorphic fea- (26.2%) with a bone-age delay of Ͼ1 year, 43 cases tures or chronic diseases were excluded; this was ensured by tests for chronic inflammatory (erythrocyte sedimentation rate, blood (20.1%) of FSS, 92 cases (43.0%) with a combination count, C-reactive protein), celiac (gliadin and endomysium anti- of both conditions, and 23 cases (10.7%) without bodies), hepatic (aspartate aminotransferase, alanine aminotrans- pronounced bone-age retardation and with normal ferase), or renal (creatinine) diseases and hypothyroidism (free target height. A summary of clinical and anthropo- thyroxin, thyrotropin). Growth-hormone deficiency was considered to be unlikely based on serum insulin-like growth factor I metric data of the 123 index patients and 91 siblings (IGF-I) and insulin-like growth factor–binding protein 3 (IGFBP-3) is given in Table 1. With respect to gender distribu- levels. tion, there was a striking imbalance in the group of index patients, with a majority of almost two thirds Data Collection being male gender, whereas no difference could be Medical histories of children and parents were recorded by found among siblings. Additionally, body height using structured and standardized interviews. All interviews and was considerably lower, by almost 1 SDS, in index clinical examinations were performed by the same physician (S.H.). Eating behavior was assessed by using the Child Eating patients. Bone-age retardation was clearly more pro- Behavior Questionnaire14 (CEBQ), an instrument that allows the nounced in index patients compared with their sib- analysis of 8 dimensions of eating style developed in 400 British lings. Between male and female siblings there was no boys and girls. Daily energy and macronutrient intake was as- difference in height SDS (mean height SDS in male sessed according to the Leeds Food Frequency Questionnaire Ϫ 15,16 siblings: 1.57; mean height SDS in female siblings: (LFFQ). Within a structured interview, we additionally asked Ϫ ϭ mothers to characterize their children as “poor eaters” or “good 1.52; P .58). eaters” by means of the following question: “Is or has your child Table 2 summarizes the data concerning the char-

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-1684 by guest on September 28, 2021 e53 TABLE 1. Baseline Characteristics of Index Patients and Their Siblings Diagnosed With ISS Index Patients (n ϭ 123) Siblings (n ϭ 91) Gender distribution, n (%) Males 76 (62%) 45 (49%) Females 47 (38%) 46 (51%) Age, y, mean Ϯ SD (range) 11.9 Ϯ 3.6 (4.8 to 18.4) 11.7 Ϯ 4.2 (3.5 to 21.3) Height, SDS, mean Ϯ SD (range) Ϫ2.3 Ϯ 0.5 (Ϫ3.6 to Ϫ1.2) Ϫ1.5 Ϯ 0.5 (Ϫ3.3 to Ϫ1.1) BMI, SDS, mean Ϯ SD (range) Ϫ0.4 Ϯ 0.8 (Ϫ2.1 to 2.5) Ϫ0.1 Ϯ 0.7 (Ϫ2.0 to 2.1) Mean bone-age retardation, y, mean Ϯ SD Ϫ1.6 Ϯ 0.9 (Ϫ3.6 to ϩ0.5) Ϫ0.8 Ϯ 1.2 (Ϫ4.4 to ϩ2.7) (range)* Maximal bone-age retardation, y, mean Ϯ Ϫ1.9 Ϯ 0.9 (Ϫ3.9 to ϩ0.3) Ϫ0.9 Ϯ 1.2 (Ϫ5.5 to ϩ2.7) SD (range)* Mid parental height, cm, mean Ϯ SD (range) 167 Ϯ 4 (157 to 178) Bone-age retardation ϭ bone age Ϫ chronological age. * In case several radiograph films including those from earlier presentations were available, the respective means and maxima were calculated.

TABLE 2. Eating Behavior and BMI of Index Patients and Siblings With ISS Item Total Sample Population Good Eaters Poor Eaters P Value for Comparison (n ϭ 213) Mean (n ϭ 122 (n ϭ 91 Between Good and (Wardle et al14) ͓57%͔) ͓43%͔) Poor Eaters Food responsiveness 1.9 2.4 2.0 1.8 .002 Satiety responsiveness 3.0 3.0 2.6 3.3 Ͻ.001 Fussiness of food 3.2 2.9 3.0 3.5 Ͻ.001 Enjoyment of food 3.2 3.9 3.5 2.8 Ͻ.001 Slowness in eating 2.9 2.8 2.6 3.1 .002 Emotional overeating 1.8 1.8 1.9 1.7 .161 Emotional undereating 2.6 3.0 2.5 2.7 .032 Desire to drink 2.0 2.8 2.1 2.0 .370 BMI, SDS Ϫ0.33 Ϫ0.11 Ϫ0.55 .003 Height, SDS Ϫ2.06 Ϫ1.81 Ϫ2.31 Ͻ.001 The study sample was subdivided into good and poor eaters (see “Subjects and Methods”). Mean scores (marginal means over families) from the CEBQ are given. Differences between good and poor eaters were tested for statistical significance by analysis of variance. acterization of eating behavior in our patients with and poor eating behavior was not associated with ISS. Initially, we compared the scores from the CEBQ significant differences in the amount or composition with reference data from the literature.14 The com- of energy intake as measured by this instrument. The plete group of patients showed a different behavior mean BMI SDS of Ϫ0.33 in the whole sample corre- from the reference sample in some respects. In par- sponds to the 37th population percentile. Both good ticular, our patients were characterized by decreased and poor eaters had mean BMI SDS values below the food responsiveness, reduced enjoyment of food, respective reference values, and the BMI SDS was emotional undereating, lower desire to drink, and significantly lower in the group of poor eaters. How- increased fussiness over food. When divided into the ever, height differed significantly between the 2 sub- 2 groups of good and poor eaters, the behavioral groups: poor eaters had a markedly lower body characteristics, which were already delineated in the height. total sample, were found to be even more consistent BMI SDS was not correlated significantly with in the subgroup of poor eaters. Poor eaters clearly chronological age. The mean BMI SDS was Ϫ0.36 for revealed lower food responsiveness, higher satiety children with pronounced bone-age delay (Ͼ1 year), responsiveness, decreased enjoyment of food, and which was slightly lower than in the group of chil- increased fussiness over food and were slower eat- dren with no or a slight delay (Ͻ1 year; mean BMI ers. To complement the analysis of eating behavior as SDS: Ϫ0.16), but this difference was not statistically assessed by the CEBQ, we used the LFFQ to estimate significant (P ϭ .13). mean daily energy intake and percent energy intake In the overall group of children with ISS, serum for fat, protein, and carbohydrates (Table 3). Good concentrations of IGF-I were lower than population

TABLE 3. Food Intake (From LFFQ) (n ϭ 103 Index Patients) for the Sample and the Subgroups of Good and Poor Eaters Total Sample Good Eaters Poor Eaters P Value for Comparison (n ϭ 103) (n ϭ 47) (n ϭ 56) Between Good and Poor Eaters Daily energy intake 8431 8314 8531 .70 % energy from fat 39.4 40.1 38.8 .23 % energy from protein 13.9 13.6 14.1 .21 % energy from carbohydrates 46.5 46.1 46.8 .54 Differences between good and poor eaters were tested for statistical significance by using the t test.

e54 EATING BEHAVIORDownloaded AND BMI from IN www.aappublications.org/news IDIOPATHIC SHORT STATUREby guest on September 28, 2021 TABLE 4. Serum Endocrine Parameter Concentrations of the Total Sample of Children With ISS and Subdivisions According to the Mother’s Description of Their Eating Style Variable Whole Sample Good Eaters Poor Eaters P Value for Comparison Between Good and Poor Eaters Leptin, SDS 0.39 0.57 0.21 .10 Ghrelin, pg/mL 1101 1081 1121 .62 IGF-1 Ϫ1.00 Ϫ0.88 Ϫ1.13 .28 IGFBP-3, SDS 0.28 0.26 0.31 .71 norms (mean SDS: Ϫ1.0; P Ͻ .001) (Table 4), whereas ment, a high percentage of our patients had already serum concentrations of IGFBP-3 were somewhat been characterized as poor eaters. When we ana- higher (mean SDS: ϩ0.3; P Ͻ .001). Leptin levels, lyzed the eating behavior in this subgroup of poor adjusted for gender, BMI, and pubertal develop- eaters compared with the good eaters, we found that ment, were significantly higher in the whole group the aforementioned pattern of eating behavior was than for population norms (mean SDS: ϩ0.39; P Ͻ even more pronounced. Additionally, satiety respon- .001). Serum levels of ghrelin could not be compared siveness was found to be higher in the subgroup of with population data, because no reference values poor eaters, and speed of eating was also reduced. were available for the test kit. The differences be- The validity of the maternal assessment is substanti- tween good and poor eaters were not significant for ated further by the findings of lower BMI and height any of the endocrinologic parameters. in the group of poor eaters. However, we are fully aware of the fact that, because of the lack of prospec- DISCUSSION tive data, these findings need to be interpreted with Our observation that short stature and bone-age caution. delay were much more pronounced in the group of Considering the deviant eating behavior in our index patients than in the group of siblings reflects children with ISS, an important next question was the fact that the more severely affected child in a whether, and by what mechanism, such an eating family is generally the one presented to the pediatric style had an impact on body weight. Indeed, we outpatient clinic. The gender distribution among our found moderately reduced BMI for the total sample index patients showed a higher percentage of boys of patients compared with German population compared with girls. In contrast, an equal gender norms, which again was more reduced in poor eat- distribution was found among the recruited siblings, ers. Thus, our data confirm the findings of Thibault suggesting that the frequency of short stature with or et al,10 who examined prepubertal children with ISS without developmental delay is similar between girls (n ϭ 79) and likewise found similarly reduced BMI and boys. The preferential presentation of affected values (BMI SDS: Ϫ0.4 Ϯ 0.1). Total energy intake boys to the pediatric endocrinologist potentially sug- and percent energy intake as fat did not differ be- gests that parents are more concerned about the de- tween good and poor eaters. Percent energy intake as velopment of their sons than their daughters. fat was similar to that observed for healthy German The CEBQ is a useful parent-rated measure of school children (unpublished data). However, the eating style for research on obesity or eating disor- validity of food frequency questionnaires is debat- ders. It allows the assessment of 8 dimensions of able. Food frequency questionnaires cannot be used eating style in children. An overall comparison of to reliably assess absolute energy intake. our total sample of children with reference ranges in It has been suggested that suboptimal nutrition in the literature14 revealed distinct differences in sev- childhood can lead to impaired development of body eral aspects of eating. Responsiveness to food was height.23 Indeed, we found that poor eaters had a clearly reduced in our patients, who did not seem to significantly lower height than the good eaters. enjoy food as much as unaffected children; they had Therefore, one could speculate that the poor eating a reduced desire to drink and tended to eat less behavior found in our patients might lead to subop- during negative emotional states. Additionally, our timal nutrition and could contribute to their short patients were somewhat more fussy (“picky”) eaters, stature and developmental delay.11,24 On the other in that they were highly selective about the range of hand, it cannot be excluded that slow growth and foods accepted. All these altered parameters of eat- development cause impaired drive for eating as long ing behavior are in keeping with a specific behav- as energy stores are sufficiently replete. Therefore, ioral pattern of eating style and, therefore, allowed the question of what comes first, reduced energy characterization of this sample of children as poor intake or slow growth, remains open. eaters. Although this comparison was made with The findings of an altered eating behavior and reference ranges from a British sample, the degree to reduced BMI in children with ISS caused us to inves- which single dimensions of eating style were altered tigate further the role of 2 important regulators of suggested that a truly distinct pattern of eating be- satiety. Leptin, the product of the ob gene, is pro- havior existed in our patient sample. duced by adipocytes and acts on the hypothalamus, We do not know how mothers of healthy children suppressing food intake and stimulating energy ex- would rate their eating behavior. However, it was penditure.25 Leptin reflects the proportion of body striking that, based solely on the mothers’ assess- fat mass, its most important determining variable.21

Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-1684 by guest on September 28, 2021 e55 Furthermore, leptin seems to play a significant role CONCLUSIONS in the initiation and progression of puberty.26 We Our clinical, behavioral, and endocrinologic find- calculated leptin SDS, adjusted for gender, BMI, and ings in children with ISS point to an altered regula- Tanner stage according to reference data (Fig 1).22 tion of appetite and energy balance. It is possible that The total sample of our children, as well as both this altered regulation could contribute to the re- subgroups of good and poor eaters, revealed mod- duced height of these children. Alternatively, a cur- erately raised serum leptin concentrations that were rently unknown factor may induce both a reduced not significantly different between the subgroups. height growth and an altered eating behavior. Among all children, we found that 13% had a leptin SDS Ͼ1.96, compared with 5% expected from a gen- ACKNOWLEDGMENTS eral population sample. It was unexpected that pa- This work was funded by German National Genome Research tients with ISS have relatively high leptin levels for Network grant NGFN 01GSO118 and the European Union (Diet their BMI, a fact that may indicate alterations in and Obesity; grant QLK1-2000-00515). We are grateful to the children and their parents for their endocrine mechanisms of satiety regulation in paral- participation in this study. lel to the observed altered eating behavior. Further- more, our results are not in accordance with obser- REFERENCES vations made by other investigators in smaller 1. Bierich JR. Constitutional delay of growth and adolescence. Baillieres 5 samples of children. Gill et al studied 23 boys with Clin Endocrinol Metab. 1992;6:573–587 CDGP and found lower BMI values only in prepu- 2. Pasquino AM, Albanese A, Bozzola M, et al. 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Downloaded from www.aappublications.org/newswww.pediatrics.org/cgi/doi/10.1542/peds.2004-1684 by guest on September 28, 2021 e57 Children With Idiopathic Short Stature Are Poor Eaters and Have Decreased Body Mass Index Stefan A. Wudy, Sandra Hagemann, Astrid Dempfle, Gundula Ringler, Werner F. Blum, Lars D. Berthold, Gerhard Alzen, Ludwig Gortner and Johannes Hebebrand Pediatrics 2005;116;e52 DOI: 10.1542/peds.2004-1684

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Children With Idiopathic Short Stature Are Poor Eaters and Have Decreased Body Mass Index Stefan A. Wudy, Sandra Hagemann, Astrid Dempfle, Gundula Ringler, Werner F. Blum, Lars D. Berthold, Gerhard Alzen, Ludwig Gortner and Johannes Hebebrand Pediatrics 2005;116;e52 DOI: 10.1542/peds.2004-1684

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